SUMMARY/ABSTRACT The field of childhood cancer research is at a crossroads. After stunning improvements, cure rates for most pediatric malignancies have plateaued. Indeed, children with metastatic solid malignancies continue to have less than a 50% chance of survival despite being treated with highly intensive chemoradiotherapy. Neuroblastoma (NB), a diverse malignancy arising from the developing sympathetic nervous system, is an outstanding model for the problem of childhood cancer in general and is the focus of this new Program Project Grant. The primary goal of this multi-institutional and multi-disciplinary Program is to achieve improved outcomes for patients with high-risk, disseminated NB by: 1) discovering basic mechanisms of resistance to modern therapies; 2) uncovering targetable vulnerabilities driving resistance; and 3) translating these insights into evidence-based clinical trials. The five proposed Projects focus on interrelated fundamental problems in the broad fields of genomics (Projects 1 and 2), epigenetics (Project 3), tumor microenvironment (all Projects) and immuno-oncology (Projects 1, 2, 4 and 5). The central hypothesis is that high-risk NBs evolve to evade therapeutic interventions but that these resistance mechanisms can be targeted therapeutically. The motivation for the proposed research is the urgent need to improve survival of patients with high-risk NB, and to decrease treatment-related morbidities. The five proposed Projects will each address three Specific Aims of the overall Program: 1) discover mechanisms of NB therapy resistance; 2) discover tumor-intrinsic and tumor- extrinsic therapeutic vulnerabilities imparted by therapy resistance; and 3) develop readily translatable therapeutic strategies to exploit de novo and acquired resistance mechanisms and molecular vulnerabilities. The Projects will each be supported by three Cores: A) Research Support Services; B) Clinical Trials and Translation; and C) Biostatistics. Unique to the Program is a mature clinical trials consortium integrated into Core B (New Approaches to NB Therapy [NANT] consortium). Critical to the success of each Project is unparalleled access to therapy resistant tumors from the NANT, and sharing of clinically relevant in vitro and murine models. Importantly, all Projects have clear milestones to deliver one or more clinical trials to the NANT, with Project specific studies designed to provide a portfolio of nonclinical data required for efficient translation to the refractory NB patient population. This highly integrated Program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, kinome reprogramming, epigenetic adaptation and immune evasion, but is steadfastly translational, as the investigative team is constituted with physicians who care for children with this disease. The significance of the proposed program is the likely discovery of fundamental mechanisms of cancer therapy resistance leading to substantively improved probability of cure coupled with reduced therapy-related morbidity for children, adolescents and adults afflicted with high-risk NB.